We are interested in understanding (1) how cells regulate their ability to adhere to one another, (2) how cell-cell adhesion complexes might also function to transduce signals that inform the cell about the state of adhesion, a process known as signal transduction, and (3) the relationship of these regulatory events to human skin disease. This application represents the competitive continuation for this grant, which is funded through May 2006. Funding of this grant over the past 5 years has enabled us to (i) better understand the cell-cell adhesion and signaling functions of keratinocyte adherens junctions and desmosomes, (ii) begin to understand how these processes are regulated by phosphorylation and O-glycosylation, and (iii) begin to define the molecular mechanisms of acantholysis in the human autoimmune blistering disease pemphigus vulgaris (PV). Funding of this grant in the prior period has led to the following significant observations: (i) phosphorylation and O-glycosylation of mammalian beta-catenin and plakoglobin regulates the cell-cell adhesion and signaling function of these proteins, (ii) keratinocyte adherens junctions and desmosomes activate intracellular signaling systems, (iii) keratinocyte desmosomes are dynamic structures, and (iv) pemphigus autoantibodies activate desmosome-mediated signaling that appears to have a role in the mechanism of acantholysis in pemphigus. Therefore, funding of this grant in the prior period has led to the identification of and demonstration that inhibition of p38 MAPK represents a novel, rational, and practical therapeutic approach to treating pemphigus vulgaris. Additionally, stabilization of keratinocyte cell-cell adhesion by increased O-glycosylation may provide an additional therapeutic approach for treating blistering diseases. In this application we outline our plan to more deeply investigate the biology of keratinocyte cell-cell adhesion and desmosome signaling by (i) further defining the desmosome signaling pathway and mechanism of PV IgG acantholysis, (ii) determining the biological role played by HSP25/27 in PV acantholysis and cell-cell adhesion transitions, (iii) determining if PF IgG similarly activates desmosome signaling and identify similarities and differences between PV IgG (dsg3) and PF IgG (dsgl) mediated desmosome signaling. A significant outcome of these studies will be to translate these observations into effective treatments for pemphigus.